The Ras/Raf/MEK/MAPK cascade is one of the major pathways transmitting signals from the cell surface to the nucleus. The Ras family of G-proteins relay signals from activated growth factor receptors to the downstream intracellular Raf family kinases, which, in turn, trigger the activation of MEK1 and MEK2 extracellular signal-regulated kinase (ERK1/ERK2) pathway. The MEK family of genes consists of five genes: MEK1, MEK2, MEK3, MEK4 and MEK5. The structure of MEK consists of an amino-terminal negative regulatory domain and a carboxy-terminal MAP kinase-binding domain, which is necessary for binding and activation of ERKs. MEK1 is a 393-amino-acid protein with a molecular weight of 44 kDa (Crews, et al., 258 SCIENCE 478-80 (1992)).
Upstream and downstream signalling of the Ras/Raf/MEK/MAPK cascade involves multiple pathways, however MEK appears to specifically phosphorylate MAPK. The role of MAPK in cancer (Reddy, et al., 22 CANCER METASTASIS REV. 395-403 (2004)), and the dysfunctional activation of signalling components in the MAPK pathway in a high proportion of tumor types, has lead to an extended interest in MEK as a cancer target and the development of MEK inhibitors (Chang et al., 17 LEUKEMIA 1263-93 (2003); Lee, et al., 38 EXP. MOL. MED. 27-35 (2006)).
Among the furthest advanced MEK inhibitors is Pfizer's PD-0325901, a diarylamine derived MEK inhibitor, that has recently entered phase II clinical trials for the potential oral treatment of cancer.
Array Biopharma's ARRY142886, a phenylamino-2-pyridone derived MEK inhibitor, is currently in Phase I clinical trials.
WO 00/42029 (Warner-Lambert Company) further reports about diarylamines (A) that exhibit MEK inhibitory activity and are potentially useful for the treatment of cancer and other proliferative diseases.

WO 04/056789 (Warner-Lambert Company) reports about oxadiazole- and thiadiazole-phenylamine derivatives (B) as MEK inhibitors for the potential treatment of inflammation and proliferative diseases.

WO 05/051301 (Array Biopharma Inc.) relates to heterocyclic compounds (C), which are MEK inhibitors and useful for the potential treatment of hyperproliferative diseases.

WO 05/000818 (Warner-Lambert Company) relates to phenylamino-2-pyridone derivatives (D) as MEK inhibitors that might be useful for the treatment of proliferative diseases.
